Antibody-based therapy is now one of the most successful and important strategies for treating patients with haematological malignancies, solid tumors, infections, rheumatic and vascular diseases. Evidence from clinical trials of antibodies in patients has revealed the importance of iterative approaches for the selection of antigen targets and optimal antibodies, including the affinity and avidity of antibodies, the choice of antibody construct, the therapeutic approach (such as signalling abrogation or immune effector function) and the need to critically examine the pharmacokinetic and pharmacodynamic properties of antibodies in early clinical trials.
Based on technologies of monoclonal antibodies generation, there are several types of therapeutic antibodies including polyclonal and monoclonal antibodies, murine, chimeric, humanized and fully human antibodies.
Monoclonal antibodies are monospecific antibodies that are made by identical immune cells that are all clones of a unique parent cell, in contrast to polyclonal antibodies which are made from several different immune cells. Monoclonal antibodies have monovalent affinity, in that they bind to the same epitope. Although serum polyclonal antibody preparations have been clinically effective in many cases, problems related to toxicity including a risk for allergic reactions, lot-to-lot variation, and uncertain dosing have limited their use. In addition, the active antigen-specific antibodies in a polyclonal preparation typically represent a relatively small portion of the total antibodies (1%); the rest of the antibodies are not only ineffective but could be even toxic or immunogenic.
The beginning of the paradigm change for antibodies began with the publication of the seminal article (Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975; 256:495-497) describing hybridoma technology which can provide unlimited quantities of monoclonal antibodies with predefined specificity. In addition, this technology was not patented and could be used freely. A major limitation of the hybridoma technology has been the inability to produce human monoclonal antibodies. Administration of murine monoclonal antibodies in humans resulted in immune responses against the foreign proteins with the generation of human anti-mouse antibodies (HAMAs). However, the advent of a number of molecular biology techniques, mostly recombinant DNA technology, and the increased understanding of the antibody structure and function led to the development of chimeric and humanized monoclonal antibodies. Finally, phage-display techniques and other techniques based on the progress of molecular biology, including the generation of transgenic animals, allowed the development of fully human antibodies; these methodologies have been extensively reviewed. Fully human monoclonal antibodies are highly desirable as therapeutics, for in addition to the advantages of being very specific for and tightly binding to their therapeutic targets, fully human antibodies avoid potential immune responses that may occur in patients receiving antibodies that contain nonhuman (typically mouse) components. However, during the last decade the basic concepts and methodologies for fully human antibody generation have not changed significantly but have been applied to numerous new targets.
It would be highly useful to the medical and scientific fields to investigate alternate strategies for generating of fully human antibodies to improve efficacy of therapy and to produce conceptually new antibodies for treatment of different diseases.